HIGHLIGHTS OF PRESCRIBING INFORMATION …...Neonatal Opioid Withdrawal Syndrome VITUZ is not...

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use VITUZ®

safely and effectively. See full prescribing information for VITUZ.

VITUZ (hydrocodone bitartrate and chlorpheniramine maleate) oral solution, CII Initial U.S. Approval: 1987

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFETHREATENING RESPIRATORY DEPRESSION; ACCIDENTAL

INGESTION; MEDICATION ERRORS; CYTOCHROME P450 3A4 INTERACTION; CONCOMITANT USE WITH

BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; INTERACTION WITH ALCOHOL; NEONATAL OPIOID

WITHDRAWAL SYNDROME

See full prescribing information for complete boxed warning. • VITUZ exposes users to risks of addiction, abuse, and misuse,

which can lead to overdose and death. Assess patient’s risk before prescribing and monitor closely for these behaviors and conditions. (5.1)

• Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or when used in patients at higher risk. (5.2)

• Accidental ingestion of VITUZ, especially by children, can result in a fatal overdose of hydrocodone. (5.2)

• Ensure accuracy when prescribing, dispensing, and administering VITUZ. Dosing errors can result in accidental overdose and death. (2,1, 5.5)

• Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of hydrocodone. Avoid the use of VITUZ in patients taking CYP3A4 inhibitors or inducers. (5.7, 7.2, 7.3)

• Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Avoid the use of VITUZ in patients taking benzodiazepines, other CNS depressants, or alcohol. (5.8, 7.5)

• Instruct patients not to consume alcohol or any products containing alcohol while taking VITUZ because co-ingestion can result in fatal plasma hydrocodone levels. (5.8, 7.1)

• VITUZ is not recommended for use in pregnant women. Prolonged use of VITUZ during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If VITUZ is used for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.13, 8.1)

---------------------------RECENT MAJOR CHANGES--------------------------Boxed Warning 6/2018 Indications and Usage (1) 6/2018 Dosage and Administration (2.1, 2.3) 6/2018 Contraindications (4) 6/2018 Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5, 5.7, 5.8, 5.9,

5.11, 5.12, 5.13, 5.14, 5.15) 6/2018

----------------------------INDICATIONS AND USAGE--------------------------VITUZ is a combination of hydrocodone, an opioid agonist; and chlorpheniramine, a histamine-1 (H1) receptor antagonist, indicated for the temporary relief of cough and upper respiratory symptoms associated with allergy or the common cold in patients 18 years of age and older. (1) Important Limitations of Use (1) • Not indicated for pediatric patients under 18 years of age. • Because of the risks of addiction, abuse, and misuse with opioids, even at

recommended doses, reserve VITUZ for use in adult patients for whom the benefits of cough suppression are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made.

------------------------DOSAGE AND ADMINISTRATION---------------------• Adults 18 years of age and older: 5 mL every 4 to 6 hours as needed, not to

exceed 4 doses (20 mL) in 24 hours. (2.2)

• Measure VITUZ with an accurate milliliter measuring device. (2.1, 5.5) • Do not increase the dose or dosing frequency. (2.1) • Prescribe for the shortest duration consistent with treatment goals. (2.3) • Reevaluate patients with unresponsive cough in 5 days or sooner for

possible underlying pathology. (2.3) • Reevaluate patient prior to refilling. (2.3)

---------------------DOSAGE FORMS AND STRENGTHS---------------------Oral solution: Each 5 mL contains hydrocodone bitartrate 5 mg; and chlorpheniramine maleate 4 mg. (3)

------------------------------CONTRAINDICATIONS------------------------------• Children younger than 6 years of age. (4) • Significant respiratory depression. (4) • Acute or severe bronchial asthma in an unmonitored setting or in absence

of resuscitative equipment. (4) • Known or suspected gastrointestinal obstruction, including paralytic ileus.

(4) • Hypersensitivity to hydrocodone, chlorpheniramine, or any of the inactive

ingredients in VITUZ. (4)

------------------------WARNINGS AND PRECAUTIONS----------------------See Boxed WARNINGS • Life-threatening respiratory depression in patients with chronic pulmonary

disease or in elderly, cachectic, or debilitated patients: Monitor closely, particularly during initiation of therapy. (5.4)

• Activities requiring mental alertness: Avoid engaging in hazardous tasks requiring mental alertness such as driving or operating machinery. (5.6)

• Risks of use in patients with head injury, impaired consciousness, increased intracranial pressure, or brain tumors: Avoid use. May increase intracranial pressure and obscure the clinical course of head injuries. (5.10)

• Seizures in patients with seizure disorders: Monitor during therapy. (5.11) • Severe hypotension: Monitor during initiation of therapy. Avoid use in

patients with circulatory shock. (5.12) • Adrenal insufficiency: If diagnosed, treat with physiologic replacement of

corticosteroids, and wean patient off of the opioid. (5.14)

------------------------------ADVERSE REACTIONS------------------------------Common adverse reactions include: Sedation (somnolence, mental clouding, lethargy), impaired mental and physical performance, lightheadedness, dizziness, headache, dry mouth, nausea, vomiting, and constipation (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hawthorn Pharmaceuticals, Inc. at 1-800-793-2145 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

------------------------------DRUG INTERACTIONS------------------------------• Phenytoin: Avoid concomitant use; may increase phenytoin levels. (7.4) • Serotonergic drugs: Concomitant use may result in serotonin syndrome.

Discontinue if serotonin syndrome is suspected. (7.6) • Monoamine Oxidase Inhibitors (MAOIs): Can potentiate the effects of

hydrocodone. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping an MAOI. (7.7)

• Muscle relaxants: Avoid concomitant use. (7.8) • Diuretics: Hydrocodone may reduce the efficacy of diuretics. Monitor for

reduced effect. (7.9) • Anticholinergic drugs: Concomitant use may cause paralytic ileus. (5.8,

7.10)

-------------------------USE IN SPECIFIC POPULATIONS---------------------• Pregnancy: Avoid use in pregnant women. May cause fetal harm. (8.1) • Lactation: Breastfeeding not recommended. (8.2) • Renal Impairment: Use with caution in patients with severe renal

impairment. (8.6) • Hepatic Impairment: Use with caution in patients with severe hepatic

impairment. (8.7)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 6/2018

Reference ID: 4281737

http://www.fda.gov/medwatch

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFETHREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; MEDICATION ERRORS; CYTOCHROME P450 3A4 INTERACTION; CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; INTERACTION WITH ALCOHOL; NEONATAL OPIOID WITHDRAWAL SYNDROME 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions 2.2 Recommended Dosage 2.3 Monitoring, Maintenance, and Discontinuation of Therapy

3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS

5.1 Addiction, Abuse, and Misuse 5.2 Life-Threatening Respiratory Depression 5.3 Risks with Use in Pediatric Populations 5.4 Risks with Use in Other At-Risk Populations 55 Risks of Accidental Overdose and Death due to Medication Errors 5.6 Activities Requiring Mental Alertness: Risks of Driving and

Operating Machinery 5.7 Risks from Concomitant Use or Discontinuation of Cytochrome

P450 3A4 Inhibitors and Inducers 58 Risks from Concomitant Use with Benzodiazepines or other CNS

Depressants 5.9 Risks of Use in Patients with Gastrointestinal Conditions 5.10 Risks of Use in Patients with Head Injury, Impaired

Consciousness, Increased Intracranial Pressure, or Brain Tumors 5.11 Increased Risk of Seizures in Patients with Seizure Disorders 5.12 Severe Hypotension 5.13 Neonatal Opioid Withdrawal Syndrome 5.14 Adrenal Insufficiency 5.15 Drug/Laboratory Test Interactions

6 ADVERSE REACTIONS

7 DRUG INTERACTIONS 7.1 Alcohol 7.2 Inhibitors of CYP3A4 and CYP2D6 7.3 CYP3A4 Inducers 7.4 Phenytoin 7.5 Benzodiazepines, and Other CNS Depressants 7.6 Serotonergic Drugs 7.7 Monoamine Oxidase Inhibitors (MAOIs) 7.8 Muscle Relaxants 7.9 Diuretics 7.10 Anticholinergic Drugs

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence

10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed.


FULL PRESCRIBING INFORMATION

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; MEDICATION ERRORS; CYTOCHROME P450

3A4 INTERACTION; CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; INTERACTION WITH ALCOHOL; NEONATAL OPIOID WITHDRAWAL

SYNDROME

Addiction, Abuse, and Misuse VITUZ exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Reserve VITUZ for use in adult patients for whom the benefits of cough suppression are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. Assess each patient’s risk prior to prescribing VITUZ, prescribe VITUZ for the shortest duration that is consistent with individual patient treatment goals, monitor all patients regularly for the development of addition or abuse, and refill only after reevaluation of the need for continued treatment. [see Warnings and Precautions (5.1)]

Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of VITUZ. Monitor for respiratory depression, especially during initiation of VITUZ therapy or when used in patients at higher risk [see Warnings and Precautions (5.2)].

Accidental Ingestion Accidental ingestion of even one dose of VITUZ, especially by children, can result in a fatal overdose of hydrocodone [see Warnings and Precautions (5.2)].

Risk of Medication Errors Ensure accuracy when prescribing, dispensing, and administering VITUZ. Dosing errors can result in accidental overdose and death. Always use an accurate milliliter measuring device when measuring and administering VITUZ [see Dosage and Administration (2.1), Warnings and Precautions (5.5)].

Cytochrome P450 3A4 Interaction The concomitant use of VITUZ with all cytochrome P450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentration. Avoid the use of VITUZ in patients taking a CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.7), Drug Interactions (7.2, 7.3)].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and


death. Avoid the use of VITUZ in patients taking benzodiazepines, other CNS depressants, or alcohol. [see Warning and Precautions (5.8), Drug Interactions (7.5)]

Interaction with Alcohol Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain alcohol while taking VITUZ. The co-ingestion of alcohol with VITUZ may result in increased plasma levels and a potentially fatal overdose of hydrocodone [see Warnings and Precautions (5.8) and Drug Interactions (7.1].

Neonatal Opioid Withdrawal Syndrome VITUZ is not recommended for use in pregnant women [see Use in Specific Populations (8.1)]. Prolonged use of VITUZ during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If VITUZ is used for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.13)]

1 INDICATIONS AND USAGE

VITUZ is indicated for the temporary relief of cough and upper respiratory symptoms associated with allergy or the common cold in patients 18 years of age and older. Important Limitations of Use • Not indicated for pediatric patients under 18 years of age [see Use in Specific Populations (8.4)]. • Contraindicated in pediatric patients less than 6 years of age [see Contraindications (4)]. • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see

Warnings and Precautions (5.1)], reserve VITUZ for use in adult patients for whom the benefits of cough suppression are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made.

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions Administer VITUZ by the oral route only. Always use an accurate milliliter measuring device when administering VITUZ to ensure that the dose is measured and administered accurately. A household teaspoon is not an accurate measuring device and could lead to overdosage [see Warnings and Precautions (5.5)]. For prescriptions where a measuring device is not provided, a pharmacist can provide an appropriate measuring device and can provide instructions for measuring the correct dose. Do not overfill. Rinse the measuring device with water after each use. Advise patients not to increase the dose or dosing frequency of VITUZ because serious adverse events such as respiratory depression may occur with overdosage [see Warnings and Precautions (5.2), Overdosage (10)]. The dosage of VITUZ should not be increased if cough fails to respond; an unresponsive cough should be reevaluated for possible underlying pathology [see Dosage and Administration (2.3), Warnings and Precautions (5.4)].


2.2 Recommended Dosage Adults 18 years of age and older: 5 mL every 4 to 6 hours as needed, not to exceed 4 doses (20 mL) in 24 hours

2.3 Monitoring, Maintenance, and Discontinuation of Therapy Prescribe VITUZ for the shortest duration that is consistent with individual patient treatment goals [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy [see Warnings and Precautions (5.2)]. Reevaluate patients with unresponsive cough in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease [see Warnings and Precautions (5.4)]. If a patient requires a refill, reevaluate the cause of the cough and assess the need for continued treatment with VITUZ, the relative incidence of adverse reactions, and the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1)]. Do not abruptly discontinue VITUZ in a physically-dependent patient [see Drug Abuse and Dependence (9.3)]. When a patient who has been taking VITUZ regularly and may be physically dependent no longer requires therapy with VITUZ, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both.

3 DOSAGE FORMS AND STRENGTHS

Oral solution: Each 5 mL contains hydrocodone bitartrate, USP, 5 mg; and chlorpheniramine maleate, USP, 4 mg. VITUZ is a clear, colorless to light yellow, grape-flavored liquid. [see Description (11)]

4 CONTRAINDICATIONS

VITUZ is contraindicated for: • All children younger than 6 years of age [see Warnings and Precautions (5.2, 5.3), Use in Specific

Populations (8.4)]. VITUZ is also contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions (5.2)]. • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

[see Warnings and Precautions (5.4)]. • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and

Precautions (5.9)]. • Hypersensitivity to hydrocodone, chlorpheniramine, or any of the inactive ingredients in VITUZ [see

Adverse Reactions (6)].

5 WARNINGS AND PRECAUTIONS

5.1 Addiction, Abuse, and Misuse VITUZ contains hydrocodone, a Schedule II controlled substance. As an opioid, VITUZ exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)], which can lead to overdose and death [see Overdosage (10)]. Reserve VITUZ for use in adult patients for whom the benefits of cough


suppression are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. Assess each patient’s risk prior to prescribing VITUZ, prescribe VITUZ for the shortest duration that is consistent with individual patient treatment goals, monitor all patients regularly for the development of addiction or abuse, and refill only after reevaluation of the need for continued treatment. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed VITUZ. Addiction can occur at recommended dosages and if the drug is misused or abused. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing VITUZ. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, including hydrocodone, one of the active ingredients in VITUZ. Hydrocodone produces dose-related respiratory depression by directly acting on the brain stem respiratory center that controls respiratory rhythm and may produce irregular and periodic breathing. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression includes discontinuation of VITUZ, close observation, supportive measures, and use of opioid antagonists (e.g. naloxone), depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of VITUZ, the risk is greatest during the initiation of therapy, when VITUZ is used concomitantly with other drugs that may cause respiratory depression [see Warnings and Precautions (5.8)], in patients with chronic pulmonary disease or decreased respiratory reserve, and in patients with altered pharmacokinetics or altered clearance (e.g. elderly, cachectic, or debilitated patients) [see Warnings and Precautions (5.4)]. To reduce the risk of respiratory depression, proper dosing of VITUZ is essential [see Dosage and Administration (2.1), Warnings and Precautions (5.5)]. Monitor patients closely, especially within the first 2472 hours of initiating therapy or when used in patients at higher risk. Overdose of hydrocodone in adults has been associated with fatal respiratory depression, and the use of hydrocodone in children younger than 6 years of age has been associated with fatal respiratory depression when used as recommended. Accidental ingestion of even one dose of VITUZ, especially by children, can result in respiratory depression and death.

5.3 Risks with Use in Pediatric Populations Children are particularly sensitive to the respiratory depressant effects of hydrocodone [see Warnings and Precautions (5.2)]. Because of the risk of life-threatening respiratory depression and death, VITUZ is contraindicated in children less than 6 years of age [see Contraindications (4)]. Use of VITUZ in children also exposes them to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)], which can lead to overdose and death [see Warnings and Precautions (5.1), Overdosage (10)]. Because the benefits of symptomatic treatment of cough associated with allergies or the common cold do not outweigh the risks of use of hydrocodone in pediatric patients, VITUZ is not indicated for use in patients younger than 18 years of age [see Indications (1), Use in Specific Populations (8.4)].


5.4 Risks in Other At-Risk Populations Unresponsive Cough The dosage of VITUZ should not be increased if cough fails to respond; an unresponsive cough should be reevaluated in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease [see Dosage and Administration (2.3)]. Asthma and Other Pulmonary Disease The use of VITUZ in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated [see Contraindications (4)]. Opioid analgesics and antitussives, including hydrocodone, one of the active ingredients in VITUZ, should not be used in patients with acute febrile illness associated with productive cough or in patients with chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on the patient’s respiratory function. VITUZ-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of VITUZ [see Warnings and Precautions (5.2)]. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.2)]. Because of the risk of respiratory depression, avoid the use of opioid antitussives, including VITUZ in patients with compromised respiratory function, patients at risk of respiratory failure, and in elderly, cachectic, or debilitated patients. If VITUZ is prescribed, monitor such patients closely, particularly when initiating VITUZ and when VITUZ is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.8)].

5.5 Risk of Accidental Overdose and Death due to Medication Errors Dosing errors can result in accidental overdose and death. To reduce the risk of overdose and respiratory depression, ensure that the dose of VITUZ is communicated clearly and dispensed accurately [see Dosage and Administration (2.1)]. Advise patients to always use an accurate milliliter measuring device when measuring and administering VITUZ. Inform patients that household teaspoon is not an accurate measuring device and such use could lead to overdosage and serious adverse reactions [see Overdosage (10)]. For prescriptions where a measuring device is not provided, a pharmacist can provide an appropriate calibrated measuring device and can provide instructions for measuring the correct dose.

5.6 Activities Requiring Mental Alertness: Risks of Driving and Operating Machinery Hydrocodone bitartrate and chlorpheniramine maleate, two of the active ingredients in VITUZ, may produce marked drowsiness and impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Advise patients to avoid engaging in hazardous tasks requiring mental alertness and motor coordination after ingestion of VITUZ. Avoid concurrent use of VITUZ with alcohol or other central nervous system depressants because additional impairment of central nervous system performance may occur [see Warnings and Precautions (5.8)].


5.7 Risks from Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of VITUZ with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azoleantifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of hydrocodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions (5.2)], particularly when an inhibitor is added after a stable dose of VITUZ is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in VITUZ-treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions. Concomitant use of VITUZ with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease hydrocodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone. Avoid the use of VITUZ in patients who are taking a CYP3A4 inhibitor or inducer. If concomitant use of VITUZ with a CYP3A4 inhibitor or inducer is necessary, monitor patients for signs and symptoms that may reflect opioid toxicity and opioid withdrawal [see Drug Interactions (7.2, 7.3)].

5.8 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants Concomitant use of opioids, including VITUZ, with benzodiazepines, or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Because of these risks, avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol [see Drug Interactions (7.1, 7.5)]. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. Because of similar pharmacologic properties, it is reasonable to expect similar risk with concomitant use of opioid cough medications and benzodiazepines, other CNS depressants, or alcohol. Advise both patients and caregivers about the risks of respiratory depression and sedation if VITUZ is used with benzodiazepines, alcohol, or other CNS depressants [see Patient Counseling Information (17)]. Patients must not consume alcoholic beverages, or prescription or non-prescription products containing alcohol, while on VITUZ therapy. The co-ingestion of alcohol with VITUZ may result in increased plasma levels and a potentially fatal overdose of hydrocodone [see Drug Interactions (7.1)].

5.9 Risks of Use in Patients with Gastrointestinal Conditions VITUZ is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see Contraindications (4)]. The use of hydrocodone in VITUZ may obscure the diagnosis or clinical course of patients with acute abdominal conditions. The concurrent use of anticholinergics with VITUZ may produce paralytic ileus [see Drug Interactions (7.10)]. The hydrocodone in VITUZ may result in constipation or obstructive bowel disease, especially in patients with underlying intestinal motility disorders. Use with caution in patients with underlying intestinal motility disorders. The hydrocodone in VITUZ may cause spasm of the sphincter of Oddi, resulting in an increase in biliary tract pressure. Opioids may cause increases in serum amylase [see Warnings and Precautions (5.15)]. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

5.10 Risks of Use in Patients with Head Injury, Impaired Consciousness, Increased Intracranial Pressure, or Brain Tumors Avoid the use of VITUZ in patients with head injury, intracranial lesions, or a pre-existing increase in intracranial pressure. In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those


with evidence of increased intracranial pressure or brain tumors), VITUZ may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Furthermore, opioids produce adverse reactions that may obscure the clinical course of patients with head injuries.

5.11 Increased Risk of Seizures in Patients with Seizure Disorders The hydrocodone and chlorpheniramine in VITUZ may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during VITUZ therapy.

5.12 Severe Hypotension VITUZ may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7.5)]. Monitor these patients for signs of hypotension after initiating VITUZ. In patients with circulatory shock, VITUZ may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of VITUZ in patients with circulatory shock.

5.13 Neonatal Opioid Withdrawal Syndrome VITUZ is not recommended for use in pregnant women. Prolonged use of VITUZ during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. [see Use in Specific Populations (8.1), Patient Counseling Information (17)]

5.14 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.15 Drug/Laboratory Test Interactions Because opioid agonists may increase biliary tract pressure, with resultant increase in plasma amylase or lipase levels, determination of these enzyme levels may be unreliable for 24 hours after administration of a dose of VITUZ.

6 ADVERSE REACTIONS

The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, abuse, and misuse [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.3)]


• Life-threatening respiratory depression [see Warnings and Precautions (5.2, 5.3, 5.4, 5.8), Overdosage (10)]

• Accidental overdose and death due to medication errors [see Warnings and Precautions (5.5)] • Decreased mental alertness with impaired mental and/or physical abilities [see Warnings and

Precautions (5.6)] • Interactions with benzodiazepines and other CNS depressants [see Warnings and Precautions (5.8),

Drug Interactions (7.1, 7.5)] • Paralytic ileus, gastrointestinal adverse reactions [see Warnings and Precautions (5.9)] • Increased intracranial pressure [see Warnings and Precautions (5.10)] • Obscured clinical course in patients with head injuries [see Warnings and Precautions (5.10)] • Seizures [see Warnings and Precautions (5.11)] • Severe hypotension [see Warnings and Precautions (5.12)] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.13)] • Adrenal insufficiency [see Warnings and Precautions (5.14)]

The following adverse reactions have been identified during clinical studies, in the literature, or during post-approval use of hydrocodone and/or chlorpheniramine. Because these reactions may be reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The most common adverse reactions to VITUZ include: Sedation (somnolence, mental clouding, lethargy), impaired mental and physical performance, lightheadedness, dizziness, headache, dry mouth, nausea, vomiting, and constipation. Other reactions include: Anaphylaxis: Anaphylaxis has been reported with hydrocodone, one of the ingredients in VITUZ. Body as a whole: Coma, death, fatigue, falling injuries, lethargy. Cardiovascular: Peripheral edema, increased blood pressure, decreased blood pressure, tachycardia, chest pain, palpitation, syncope, orthostatic hypotension, prolonged QT interval, hot flush. Central Nervous System: Ataxia, facial dyskinesia, insomnia, migraine, increased intracranial pressure, seizure, tremor, tinnitus, vertigo. Dermatologic: Flushing, hyperhidrosis, pruritus, rash. Endocrine/Metabolic: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)]. Gastrointestinal: Abdominal pain, bowel obstruction, decreased appetite, diarrhea, difficulty swallowing, GERD, indigestion, pancreatitis, paralytic ileus, biliary tract spasm (spasm of the sphincter of Oddi). Genitourinary: Urinary tract infection, ureteral spasm, spasm of vesicle sphincters, urinary retention. Hematologic: Agranulocytosis, aplastic anemia, and thrombocytopenia have been reported. Laboratory: Increases in serum amylase. Musculoskeletal: Arthralgia, backache, muscle spasm. Ophthalmic: Miosis (constricted pupils), visual disturbances, blurred vision, diplopia. Psychiatric: Agitation, anxiety, confusion, fear, dysphoria, depression, hallucinations.


Reproductive: Hypogonadism, infertility. Respiratory: Bronchitis, cough, dyspnea, nasal congestion, nasopharyngitis, respiratory depression, sinusitis, upper respiratory tract infection, thickening of bronchial secretions, tightness of chest and wheezing, dry nose, dry throat. Other: Drug abuse, drug dependence, opioid withdrawal syndrome.

7 DRUG INTERACTIONS

No specific drug interaction studies have been conducted with VITUZ.

7.1 Alcohol Concomitant use of alcohol with VITUZ can result in an increase of hydrocodone plasma levels and potentially fatal overdose of hydrocodone. Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products containing alcohol while on VITUZ therapy [see Warnings and Precautions (5.8), Clinical Pharmacology (12.3).

7.2 Inhibitors of CYP3A4 and CYP2D6 The concomitant use of VITUZ and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), or protease inhibitors (e.g., ritonavir), can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of VITUZ and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of VITUZ is achieved [see Warnings and Precautions (5.7)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to hydrocodone. Avoid the use of VITUZ while taking a CYP3A4 or CYP2D6 inhibitor. If concomitant use is necessary, monitor patients for respiratory depression and sedation at frequent intervals.

7.3 CYP3A4 Inducers The concomitant use of VITUZ and CYP3A4 inducers such as rifampin, carbamazepine, or phenytoin, can decrease the plasma concentration of hydrocodone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone [see Warnings and Precautions (5.7)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Avoid the use of VITUZ in patients who are taking CYP3A4 inducers. If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy.

7.4 Phenytoin Adverse event reports in the literature suggest a possible drug interaction involving increased serum phenytoin levels and phenytoin toxicity when chlorpheniramine and phenytoin are co-administered. The exact mechanism for this interaction is not known, however it is believed that chlorpheniramine may inhibit the hepatic metabolism of phenytoin. Avoid the use of VITUZ in patients who are taking phenytoin.

7.5 Benzodiazepines, and Other CNS Depressants Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics,


antipsychotics, and other opioids, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Avoid the use of VITUZ in patients who are taking benzodiazepines or other CNS depressants [see Warnings and Precautions (5.8)], and instruct patients to avoid consumption of alcohol while on VITUZ [see Drug Interactions (7.1), Patient Counseling Information (17)].

7.6 Serotonergic Drugs The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation. Discontinue VITUZ if serotonin syndrome is suspected.

7.7 Monoamine Oxidase Inhibitors (MAOIs) Avoid the use of VITUZ in patients who are taking monoamine oxidase inhibitors (MAOIs) or have taken MAOIs within 14 days. The use of MAOIs or tricyclic antidepressants with hydrocodone, one of the active ingredients in VITUZ, may increase the effect of either the antidepressant or hydrocodone. MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).

7.8 Muscle Relaxants Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Avoid the use of VITUZ in patients taking muscle relaxants. If concomitant use is necessary, monitor patients for signs of respiratory depression that may be greater than otherwise expected.

7.9 Diuretics Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

7.10 Anticholinergic Drugs The concomitant use of anticholinergic drugs with VITUZ may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus [see Warnings and Precautions (5.9)]. Monitor patients for signs of urinary retention or reduced gastric motility when VITUZ is used concomitantly with anticholinergic drugs. Additive adverse effects resulting from cholinergic blockade (e.g., xerostomia, blurred vision, or constipation) may occur when anticholinergic drugs are administered with chlorpheniramine.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Risk Summary VITUZ is not recommended for use in pregnant women, including during or immediately prior to labor. Prolonged use of opioids during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.13), Clinical Considerations]. There are no available data with VITUZ use in pregnant women to inform a drug-associated risk for adverse developmental outcomes. Published studies with hydrocodone have reported inconsistent findings and have important methodological limitations (see Data). Reproductive toxicity studies have not been conducted with VITUZ; however, studies are available with individual active ingredients or related active ingredients (see Data).


In animal reproduction studies, hydrocodone administered by the subcutaneous route to pregnant hamsters during the period of organogenesis produced a teratogenic effect at a dose approximately 70 times the maximum recommended human dose (MRHD) (see Data). Chlorpheniramine administered by the oral route to mice throughout pregnancy was embryolethal at a dose approximately 9 times the MRHD and decreased postnatal survival when dosing was continued after parturition. Chlorpheniramine administered by the oral route to male and female rats prior to mating produced embryolethality at a dose approximately 9 times the MRHD (see Data). Based on the animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations

Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.12)]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Opioids, including VITUZ, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioids during labor for signs of excess sedation and respiratory depression. Data Human Data

Hydrocodone A limited number of pregnancies have been reported in published observational studies and postmarketing reports describing hydrocodone use during pregnancy. However, these data cannot definitely establish or exclude any drug-associated risk during pregnancy. Methodological limitations of these observational studies include small sample size and lack of details regarding dose, duration and timing of exposure.

Chlorpheniramine The majority of studies examining the use of chlorpheniramine in pregnancy did not find an association with an increased risk of congenital anomalies. In the few studies reporting an association, there was no consistent pattern of malformations noted. Animal Data Reproductive toxicity studies have not been conducted with VITUZ; however, studies are available with individual active ingredients or related active ingredients.


Hydrocodone In an embryofetal development study in pregnant hamsters dosed on gestation day 8 during the period of organogenesis, hydrocodone induced cranioschisis, a malformation, at approximately 70 times the MRHD (on a mg/m2 basis with a maternal subcutaneous dose of 102 mg/kg). Reproductive toxicology studies were also conducted with codeine, an opiate related to hydrocodone. In an embryofetal development study in pregnant rats dosed throughout the period of organogenesis, codeine increased resorptions and decreased fetal weights at a dose approximately 95 times the MRHD of hydrocodone (on a mg/m2 basis with a maternal oral dose of codeine at 120 mg/kg/day); however, these effects occurred in the presence of maternal toxicity. In embryofetal development studies with pregnant rabbits and mice dosed throughout the period of organogenesis, codeine produced no adverse developmental effects at doses approximately 50 and 240 times, respectively, the MRHD of hydrocodone (on a mg/m2 basis with maternal oral doses of codeine at 30 mg/kg/day in rabbits and 600 mg/kg/day in mice).

Chlorpheniramine In embryofetal development studies with pregnant rats and rabbits dosed throughout the period of organogenesis, chlorpheniramine produced no adverse developmental effects at oral doses up to approximately 35 and 45 times, respectively, the MRHD on a mg/m2 basis. However, in a reproduction study with pregnant mice dosed throughout pregnancy, chlorpheniramine produced embryolethality at a dose approximately 9 times the MRHD (on a mg/m2 basis with a maternal oral dose of 20 mg/kg/day) and decreased postnatal survival when dosing was continued after parturition. In a fertility and reproduction study with male and female rats dosed prior to mating, chlorpheniramine produced embryolethality at a dose approximately 9 times the MRHD (on a mg/m2 basis with an oral parental dose of 10 mg/kg/day).

8.2 Lactation Risk Summary Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with VITUZ. There are no data on the presence of VITUZ in human milk, the effects of VITUZ on the breastfed infant, or the effects of VITUZ on milk production; however, data are available with hydrocodone and chlorpheniramine. Hydrocodone Hydrocodone is present in breast milk. Published cases report variable concentrations of hydrocodone and hydromorphone (an active metabolite) in breast milk with administration of immediate-release hydrocodone to nursing mothers in the early post-partum period with relative infant doses of hydrocodone ranging between 1.4 and 3.7%. There are case reports of excessive sedation and respiratory depression in breastfed infants exposed to hydrocodone. No information is available on the effects of hydrocodone on milk production. Chlorpheniramine Chlorpheniramine is present in human milk. Chlorpheniramine has not been reported to cause effects on the breastfed infant. The published literature suggests that chlorpheniramine may decrease milk production based on its anticholinergic effects. (see Clinical Considerations) Clinical Considerations Infants exposed to VITUZ through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid is stopped, or when breastfeeding is stopped.


8.3 Females and Males of Reproductive Potential Infertility Chronic use of opioids, such as hydrocodone, a component of VITUZ, may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6), Clinical Pharmacology (12.2)].

8.4 Pediatric Use VITUZ is not indicated for use in patients younger than 18 years of age because the benefits of symptomatic treatment of cough associated with allergies or the common cold do not outweigh the risks for use of hydrocodone in these patients [see Indications (1), Warnings and Precautions (5.3)]. Life-threatening respiratory depression and death have occurred in children who received hydrocodone [see Warnings and Precautions (5.2)]. Because of the risk of life-threatening respiratory depression and death, VITUZ is contraindicated in children less than 6 years of age [see Contraindications (4)].

8.5 Geriatric Use Clinical studies have not been conducted with VITUZ in geriatric populations. Use caution when considering the use of VITUZ in patients 65 years of age or older. Elderly patients may have increased sensitivity to hydrocodone; greater frequency of decreased hepatic, renal, or cardiac function; or concomitant disease or other drug therapy [see Warnings and Precautions (5.4)]. Respiratory depression is the chief risk for elderly patients treated with opioids, including VITUZ. Respiratory depression has occurred after large initial doses of opioids were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration [see Warnings and Precautions (5.4, 5.8)]. Hydrocodone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, monitor these patients closely for respiratory depression, sedation, and hypotension.

8.6 Renal Impairment The pharmacokinetics of VITUZ has not been characterized in patients with renal impairment. Patients with renal impairment may have higher plasma concentrations than those with normal function [see Clinical Pharmacology (12.3)]. Chlorpheniramine maleate is cleared substantially by the kidney. As such, impaired renal function could potentially lead to the risk of decreased clearance and thereby increased retention or systemic levels of chlorpheniramine. Therefore, VITUZ should be used with caution in patients with severe impairment of renal function, and patients should be monitored closely for signs of hydrocodone toxicity (respiratory depression, sedation, and hypotension) and chlorpheniramine toxicity.

8.7 Hepatic Impairment The pharmacokinetics of VITUZ has not been characterized in patients with hepatic impairment. Patients with severe hepatic impairment may have higher plasma concentrations than those with normal hepatic function [see Clinical Pharmacology (12.3)]. Chlorpheniramine maleate is extensively metabolized by liver before elimination from the body. As such, impaired hepatic function could potentially lead to the risk of decreased metabolism and thereby increased systemic levels of chlorpheniramine. Therefore, VITUZ should be used with caution in patients with severe impairment of hepatic function, and patients should be monitored closely for signs of hydrocodone toxicity (respiratory depression, sedation, and hypotension) and chlorpheniramine toxicity.


9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance VITUZ contains hydrocodone, a Schedule II controlled substance.

9.2 Abuse Hydrocodone VITUZ contains hydrocodone, a substance with a high potential for abuse similar to other opioids including morphine and codeine. VITUZ can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)]. All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic and antitussive products carries the risk of addiction even under appropriate medical use. Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating health care provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. VITUZ, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of VITUZ VITUZ is for oral use only. Abuse of VITUZ poses a risk of overdose and death. The risk is increased with concurrent use of VITUZ with alcohol and other central nervous system depressants [see Warnings and Precautions (5.8), Drug Interactions (7.1, 7.5)]. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

9.3 Dependence Psychological dependence, physical dependence, and tolerance may develop upon repeated administration of opioids; therefore, VITUZ should be prescribed and administered for the shortest duration that is consistent with


individual patient treatment goals and patients should be reevaluated prior to refills [see Dosage and Administration (2.3), Warnings and Precautions (5.1)]. Physical dependence, the condition in which continued administration of the drug is required to prevent the appearance of a withdrawal syndrome, assumes clinically significant proportions only after several weeks of continued oral opioid use, although some mild degree of physical dependence may develop after a few days of opioid therapy. If VITUZ is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

10 OVERDOSAGE

Clinical Presentation Hydrocodone Acute overdose with hydrocodone is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, partial or complete airway obstruction, atypical snoring, hypotension, circulatory collapse, cardiac arrest, and death. Hydrocodone may cause miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)]. Chlorpheniramine Signs and symptoms of chlorpheniramine overdosage may vary from central nervous system depression to stimulation. Central toxic effects are characterized by agitation, anxiety, delirium, disorientation, hallucinations, hyperactivity, sedation, and seizures. Severe overdosage may produce coma, medullary paralysis, and death. Peripheral toxicity includes hypertension, tachycardia, dysrhythmias, vasodilation, hyperpyrexia, mydriasis, urinary retention, and diminished gastrointestinal motility. Atropine-like signs and symptoms (dry mouth, fixed dilated pupils, flushing, tachycardia, hallucinations, gastrointestinal symptoms, convulsions, urinary retention, cardiac arrhythmias and coma) may be observed. Impaired secretion from sweat glands following toxic doses of drugs with anticholinergic side effects may predispose to hyperthermia. Toxic psychosis, a possible class effect from overdose of sedating antihistamines, has been reported. Treatment of Overdose Treatment of overdosage is driven by the overall clinical presentation, and consists of discontinuation of VITUZ together with institution of appropriate therapy. Give primary attention to the reestablishment of adequate respiratory exchange through provision of a patent and protected airway and the institution of assisted or


controlled ventilation. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques. Gastric emptying may be useful in removing unabsorbed drug. The opioid antagonists, naloxone and nalmefene, are specific antidotes for respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to hydrocodone overdose, administer an opioid antagonist. An antagonist should not be administered in the absence of clinically significant respiratory depression. Because the duration of opioid reversal is expected to be less than the duration of action of hydrocodone in VITUZ, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information. Hemodialysis is not routinely used to enhance the elimination of hydrocodone or chlorpheniramine from the body. Urinary excretion of chlorpheniramine is increased when the pH of the urine is acidic; however, acid diuresis is NOT recommended to enhance elimination in overdose, as the risks of acidemia and acute tubular necrosis in patients with rhabdomyolysis far outweigh any potential benefits.

11 DESCRIPTION

VITUZ (hydrocodone bitartrate and chlorpheniramine maleate) oral solution contains hydrocodone, an opioid agonist and chlorpheniramine, a histamine-1 (H1) receptor antagonist. Each 5 mL of VITUZ contains 5 mg of hydrocodone bitartrate and 4 mg of chlorpheniramine maleate for oral administration. VITUZ also contains the following inactive ingredients: citric acid anhydrous, glycerin, grape flavor, methylparaben, propylene glycol, propylparaben, purified water, sodium citrate, sodium saccharin, and sucrose. Hydrocodone Bitartrate

The chemical name for hydrocodone bitartrate is morphinan-6-one, 4,5-epoxy-3-methoxy-17-methyl-, (5α)-, [R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1), hydrate (2:5). It is also known as 4,5α-Epoxy-3-methoxy-17methylmorphinan-6-one tartrate (1:1) hydrate (2:5). It occurs as a fine white crystal or crystalline powder, which is derived from the opium alkaloid, thebaine; and it has the following chemical structure:

CH3 N

HO H O

O OH3CO Hydrocodone Bitartrate C18H21NO3 C4H6O6 2.5 H2O Molecular weight = 494.5

O HO H

OH 2.5 H2OHO


Chlorpheniramine Maleate The chemical name for chlorpheniramine maleate is 2-pyridinepropanamine, γ-(4-chlorophenyl)-N,N-dimethyl-, (Z)-2-butenedioate (1:1). It has the following chemical structure:

Cl

N N

CH3

CH3

H

HO2C CO2H

Chlorpheniramine Maleate C16H19ClN2 C4H4O4 Molecular weight = 390.86

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action Hydrocodone Hydrocodone is an opioid agonist with relative selectivity for the mu-opioid receptor, although it can interact with other opioid receptors at higher doses. The precise mechanism of action of hydrocodone and other opiates is not known; however, hydrocodone is believed to act centrally on the cough center. In excessive doses, hydrocodone will depress respiration. Chlorpheniramine Chlorpheniramine is a propylamine derivative antihistamine (H1-receptor antagonist) of the alkylamine class that also possesses anticholinergic and sedative activity. It prevents released histamine from dilating capillaries and causing edema of the respiratory mucosa.

12.2 Pharmacodynamics Hydrocodone Effects on the Central Nervous System Hydrocodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and to electrical stimulation. Hydrocodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Hydrocodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are


decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System Hydrocodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6)]. Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Adverse Reaction Relationships There is a relationship between increasing hydrocodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions.

12.3 Pharmacokinetics Absorption After oral administration, hydrocodone had mean (SD) peak plasma concentration of 10.6 (2.63) ng/mL at 1.4 (0.55) hours. Food has no significant effect on the extent of absorption of hydrocodone. Chlorpheniramine had mean (SD) peak plasma concentration of 7.20 (1.98) ng/mL at 3.5 (1.6) hours post administration. Distribution Although the extent of protein binding of hydrocodone in human plasma has not been definitively determined, structural similarities to related opioid analgesics suggest that hydrocodone is not extensively protein bound. As most agents in the 5-ring morphinan group of semi-synthetic opioids bind plasma protein to a similar degree (range 19% [hydromorphone] to 45% [oxycodone]), hydrocodone is expected to fall within this range. Chlorpheniramine is widely distributed throughout the tissues of the body, including the central nervous system. It reportedly has an apparent steady-state volume of distribution of approximately 3.2 L/kg in adults and children and is about 70% bound to plasma proteins. Chlorpheniramine and its metabolites likely cross the placental barrier and are excreted into human breast milk.


Elimination Metabolism Hydrocodone exhibits a complex pattern of metabolism, including N-demethylation, O-demethylation, and 6keto reduction to the corresponding 6-α-and 6-β-hydroxy metabolites. CYP3A4 mediated N-demethylation to norhydrocodone is the primary metabolic pathway of hydrocodone with a lower contribution from CYP2D6 mediated O-demethylation to hydromorphone. Hydromorphone is formed from the O-demethylation of hydrocodone and may contribute to the total analgesic effect of hydrocodone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs [see Drug Interactions (7.X)]. Published in vitro studies have shown that N-demethylation of hydrocodone to form norhydrocodone can be attributed to CYP3A4 while O-demethylation of hydrocodone to hydromorphone is predominantly catalyzed by CYP2D6 and to a lesser extent by an unknown low affinity CYP enzyme. Chlorpheniramine is rapidly and extensively metabolized via demethylation in the liver, forming mono-and didesmethyl derivatives. Oxidative metabolism of chlorpheniramine is catalyzed by cytochrome P-450 2D6 Excretion Hydrocodone and its metabolites are eliminated primarily in the kidneys. The mean plasma half-life of hydrocodone is approximately 4 hours. Chlorpheniramine and its metabolites are primarily excreted through the kidneys, with large individual variation. Urinary excretion depends on urine pH and flow rate. The mean plasma half-life of chlorpheniramine is approximately 21-24 hours.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity, and fertility studies have not been conducted with VITUZ; however, published information is available for the individual active ingredients or related active ingredients. Hydrocodone Carcinogenicity studies were conducted with codeine, an opiate related to hydrocodone. Two-year studies in F344/N rats and B6C3F1 mice were conducted to assess the carcinogenic potential of codeine. No evidence of tumorigenicity was observed in male and female rats at codeine dietary doses up to 70 and 80 mg/kg/day (approximately equivalent to 55 and 65 times the MRHD of hydrocodone on a mg/m2 basis, respectively). No evidence of tumorigenicity was observed in male and female mice at codeine dietary doses up to 400 mg/kg/day (approximately equivalent to 160 times the MRHD of hydrocodone on a mg/m2 basis). Mutagenicity studies with hydrocodone have not been conducted. Fertility studies with hydrocodone have not been conducted. Chlorpheniramine Carcinogenicity studies were conducted with chlorpheniramine maleate. Two-year studies in F344/N rats and B6C3F1 mice were conducted to assess the carcinogenic potential of chlorpheniramine. No evidence of tumorigenicity was observed in male and female rats at chlorpheniramine oral doses up to 30 and 60 mg/kg/day for 5 days/week (approximately equivalent to 25 and 50 times the MRHD on a mg/m2 basis, respectively). No evidence of tumorigenicity was observed in male and female mice at chlorpheniramine oral doses up to 50 and 200 mg/kg/day for 5 days/week (approximately equivalent to 20 and 85 times the MRHD on a mg/m2 basis, respectively).


Chlorpheniramine maleate was not mutagenic in the in vitro bacterial reverse mutation assay or the in vitro mouse lymphoma forward mutation assay. Chlorpheniramine maleate was clastogenic in the in vitro Chinese hamster ovary (CHO) cell chromosomal aberration assay. Chlorpheniramine maleate had no effects on fertility in rats and rabbits at oral doses approximately 35 and 45 times the MRHD on a mg/m2 basis, respectively.

16 HOW SUPPLIED/STORAGE AND HANDLING

VITUZ (hydrocodone bitartrate and chlorpheniramine maleate) [5 mg/4 mg per 5 mL] is a clear, colorless to light yellow, grape-flavored oral solution containing 5 mg hydrocodone bitartrate and 4 mg chlorpheniramine maleate in each 5 mL supplies as: White HDPE bottles of one pint (480 mL): NDC 63717-877-16

Store solution at 20° to 25°C (68° to 77°F). [USP Controlled Room Temperature.] Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure. Ensure that patients have an oral dosing dispenser that measures the appropriate volume in milliliters. Counsel patients on how to utilize an oral dosing dispenser and correctly measure the oral suspension as prescribed.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Addiction, Abuse, and Misuse Inform patients that the use of VITUZ, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share VITUZ with others and to take steps to protect VITUZ from theft or misuse. Important Dosing and Administration Instructions Instruct patients how to measure and take the correct dose of VITUZ. Advise patients to measure VITUZ with an accurate milliliter measuring device. Patients should be informed that a household teaspoon is not an accurate measuring device and could lead to overdosage. Advise patients to ask their pharmacist to recommend an appropriate measuring device and for instructions for measuring the correct dose [see Dosage and Administration (2.1), Warnings and Precautions (5.5)]. Advise patients not to increase the dose or dosing frequency of VITUZ because serious adverse events such as respiratory depression may occur with overdosage [see Warnings and Precautions (5.2), Overdosage (10)]. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting VITUZ and that it can occur even at recommended dosages [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store VITUZ securely and to properly dispose of unused VITUZ in accordance with the local state guidelines and/or regulations.


Activities Requiring Mental Alertness Advise patients to avoid engaging in hazardous tasks that require mental alertness and motor coordination such as operating machinery or driving a motor vehicle as VITUZ may produce marked drowsiness [see Warnings and Precautions (5.6)]. Interactions with Benzodiazepines and Other Central Nervous System Depressants, Including Alcohol Inform patients and caregivers that potentially fatal additive effects may occur if VITUZ is used with benzodiazepines or other CNS depressants, including alcohol. Advise patients to avoid concomitant use of VITUZ with benzodiazepines or other CNS depressants and instruct patients not to consume alcoholic beverages, as well as prescription and over-the-counter products that contain alcohol, during treatment with VITUZ [see Warnings and Precautions (5.8), Drug Interactions (7.1, 7.5)]. Constipation Advise patients of the potential for severe constipation [see Warnings and Precautions (5.9), Adverse Reactions (6)]. Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in VITUZ. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)]. MAOI Interaction Inform patients not to take VITUZ while using or within 14 days of stopping any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking VITUZ [see Drug Interactions (7.7)]. Hypotension Inform patients that VITUZ may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.12)]. Pregnancy Advise patients that use of VITUZ is not recommended during pregnancy [see Use in Specific Populations (8.1)]. Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that use of VITUZ during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.13), Use in Specific Populations (8.1)]. Embryo-Fetal Toxicity Inform female patients of reproductive potential that VITUZ can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)]. Lactation Advise women that breastfeeding is not recommended during treatment with VITUZ [see Use in Specific Populations (8.2)].


Infertility Inform patients that chronic use of opioids, such as hydrocodone, a component of VITUZ, may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)]. Adrenal Insufficiency Inform patients that VITUZ could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.14)]. Serotonin Syndrome Inform patients that VITUZ could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications. [see Adverse Reactions (6), Drug Interactions (7.6)]. Disposal of Unused VITUZ Advise patients to properly dispose of unused VITUZ. Advise patients to throw the drug in the household trash following these steps. 1) Remove them from their original containers and mix them with an undesirable substance, such as used coffee grounds or kitty litter (this makes the drug less appealing to children and pets, and unrecognizable to people who may intentionally go through the trash seeking drugs). 2) Place the mixture in a sealable bag, empty can, or other container to prevent the drug from leaking or breaking out of a garbage bag, or to dispose of in accordance with local state guidelines and/or regulations.

Manufactured for: Hawthorn Pharmaceuticals, Inc., Morristown, NJ 07960

VITUZ Oral Solution is a Registered Trademark of Hawthorn Pharmaceuticals, Inc. Copyright ©2018 Hawthorn Pharmaceuticals, Inc. HI279 6/2018


MEDICATION GUIDE VITUZ® (Vahy-tooz)

(hydrocodone bitartrate and chlorpheniramine maleate) oral solution, C-II What is the most important information I should know about VITUZ? VITUZ is not for children under 18 years of age. VITUZ can cause serious side effects, including: • Addiction, abuse and misuse. Taking VITUZ or other medicines that contain an opioid can cause addiction,

abuse and misuse, which can lead to overdose and death. This can happen even if you take VITUZ exactly as prescribed by your healthcare provider. Your risk of addiction, abuse, and misuse is increased if you or a family member has a history of drug or alcohol abuse or addiction, or mental health problems. o Do not share your VITUZ with other people. o Keep VITUZ in a safe place away from children.

• Life-threatening breathing problems (respiratory depression). VITUZ can cause breathing problems (respiratory depression) that can happen at any time during treatment and can lead to death. Your risk of breathing problems is greatest when you first start taking VITUZ, are taking other medicines that can cause breathing problems, have certain lung problems, are elderly or have certain other health problems. Children are at higher risk for respiratory depression. Breathing problems can happen even if you take VITUZ exactly as prescribed by your healthcare provider. Call your healthcare provider or get emergency medical help right away if anyone taking VITUZ has any of the symptoms below: o increased sleepiness o shallow breathing o confusion o limpness o difficulty breathing Keep VITUZ in a safe place away from children. Accidental use of even 1 dose of VITUZ, especially by a child, is a medical emergency and can cause breathing problems (respiratory depression) which can lead to death. If a child accidentally takes VITUZ, get emergency medical help right away.

• Overdose and death due to medicine dosing errors. Overdose and death can happen if you measure the wrong dose of VITUZ. Always use an accurate milliliter (mL) measuring device to measure the correct amount of VITUZ. Do not use a household teaspoon to measure your medicine. You may accidentally take too much. You can ask your pharmacist for the measuring device you should use and how to measure the correct dose.

• Breathing problems (respiratory depression) that can lead to death and opioid withdrawal can happen if you start taking or stop taking other medicines while taking VITUZ, including: o certain antibiotics o certain medicines to treat a fungal infection o certain medicines to treat Human Immunodeficiency Virus (HIV)-1 infection, Acquired Immune Deficiency

Syndrome (AIDS), or Hepatitis C o rifampin o carbamazepine o phenytoin Tell your healthcare provider if you take any of these medicines. Ask your healthcare provider or pharmacist if you are not sure if your medicine is listed above.

• Severe drowsiness, breathing problems (respiratory depression), coma and death can happen in people who take VITUZ with benzodiazepines or other central nervous system depressants, including alcohol. o Do not take benzodiazepines or any medicine that can cause drowsiness or sleepiness during treatment with

VITUZ. o Do not drink alcohol or take prescription or over-the-counter medicines that contain alcohol during treatment

with VITUZ. • Opioid withdrawal in a newborn. Use of VITUZ during pregnancy can cause withdrawal symptoms in your

newborn baby that could be life-threatening if not recognized and treated. You should not take VITUZ if you are pregnant. Tell your healthcare provider right away if you are pregnant or think you may be pregnant.

What is VITUZ? • VITUZ is a prescription medicine used in adults to treat cough and upper respiratory symptoms that you can have

with allergies or a common cold. VITUZ contains 2 medicines, hydrocodone and chlorpheniramine. Hydrocodone is an opioid (narcotic) cough suppressant. Chlorpheniramine is an antihistamine.

• VITUZ is a federal controlled substance (C-II) because it contains hydrocodone that can be abused or lead to dependence. Keep VITUZ in a safe place to prevent misuse and abuse. Selling or giving away VITUZ may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs.


Who should not take VITUZ? VITUZ is not for children under 18 years of age. See “What is the most important information I should know about VITUZ?” Do not take VITUZ if you: • have severe breathing problems (respiratory depression) or breathing problems caused by asthma. Your child

could have breathing problems (respiratory depression) that could lead to death. See “What is the most important information I should know about VITUZ?”

• have a blockage (obstruction) in your bowel such as a paralytic ileus. • are allergic to hydrocodone, chlorpheniramine, or any of the ingredients in VITUZ. See the end of this Medication

Guide for a complete list of ingredients. Ask your healthcare provider if you have any questions about this information. Before you take VITUZ, tell your healthcare provider about all of your medical conditions, including if you: • have a drug addiction • have lung or breathing problems • have a fever and are coughing up mucus • have had a recent head injury • have had a brain tumor or other brain problems • have or have had seizures • have pain in your stomach-area (abdomen) • have constipation or other bowel problems

• have bile duct or pancreas problems • have prostate problems • have problems with your urinary tract or difficulty

urinating • have kidney or liver problems • have adrenal gland problems • have low blood pressure • plan to have surgery

• are pregnant or plan to become pregnant. VITUZ can harm your unborn baby. See “What is the most important information I should know about VITUZ?”

• are breastfeeding or plan to breastfeed. Hydrocodone and chlorpheniramine pass into your breast milk and can cause serious side effects in your baby including increased sleepiness, breathing problems (respiratory depression), and death. You and your healthcare provider should decide if you will take VITUZ or breastfeed. You should not do both. See “What should I avoid while taking VITUZ?”

• plan to have children. VITUZ may affect the ability to have a child in females and males (fertility problems). It is not known if these fertility problems will be reversible, even after you stop taking VITUZ. Talk to your healthcare provider if this is a concern for you.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking VITUZ with certain other medicines can cause side effects or affect how well VITUZ or the other medicines work. Do not start or stop taking other medicines without talking to your healthcare provider. Especially tell your healthcare provider if you: • See “What is the most important information I should know about VITUZ?” • take pain medicines such as opioids (narcotics). • take cold or allergy medicines that contain antihistamines or cough suppressants. • drink alcohol. • take muscle relaxants. • take certain medicines used to treat mood, anxiety, psychotic or thought disorders, or depression, including

monoamine oxidase inhibitors (MAOIs), tricyclics, selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors (SNRIs), or antipsychotics.

• take medicines to lower your blood pressure. • take water pills (diuretics). • take medicines called “anticholinergics” used to treat health problems such as asthma, chronic obstructive

pulmonary disease (COPD), or stomach problems. • take a medicine called “phenytoin” used to treat seizures or epilepsy. Ask your healthcare provider if you are not sure if you take any of these medicines. How should I take VITUZ? • See “What is the most important information I should know about VITUZ?” • Take VITUZ exactly as your healthcare provider tells you to take it. Do not change your dose without talking to

your healthcare provider. • Take VITUZ by mouth only. • Take VITUZ using an accurate milliliter (mL) measuring device. If you do not have one, ask your pharmacist to

give you a measuring device to help you measure the correct amount of VITUZ. Do not use a household teaspoon to measure your medicine. You may accidently take too much.

• Do not overfill your measuring device. • Rinse your measuring device with water after each use. • If you take too much VITUZ, call your healthcare provider or go to the nearest hospital emergency room right away.


• Tell your healthcare provider if your cough does not get better within 5 days of treatment with VITUZ. What should I avoid while taking VITUZ? • Avoid driving a car or operating machinery during treatment with VITUZ. VITUZ can cause you to be drowsy, slow

your thinking and motor skills, and affect your vision. • Do not drink alcohol during treatment with VITUZ. Drinking alcohol can increase your chances of having serious

side effects. Avoid the use of VITUZ if you: • are pregnant. Use of VITUZ during pregnancy can cause withdrawal symptoms in your newborn baby that could

be life-threatening if not recognized and treated. Tell your healthcare provider right away if you are pregnant or think you may be pregnant.

• are breastfeeding. Use of VITUZ while breastfeeding can cause severe breathing problems (respiratory depression) in your breastfed infant that could be life-threatening.

• take a medicine called a monoamine oxidase inhibitor (MAOI). Avoid taking an MAOI within 14 days after you stop taking VITUZ. Avoid starting VITUZ if you stopped taking an MAOI in the last 14 days.

What are the possible side effects of VITUZ? VITUZ can cause serious side effects, including: • See “What is the most important information I should know about VITUZ?” • Bowel problems including severe constipation or stomach pain. See “Who should not take VITUZ?” • Increased pressure in your head (intracranial). Avoid the use of VITUZ if you have a head injury or have been

told that you have changes in the tissue of your brain (brain lesions) or increased pressure in your head. • Increased risk of seizures in people with seizure disorders. If you have a seizure disorder, VITUZ may

increase how often you have a seizure. • Low blood pressure. A sudden drop in blood pressure can happen in some people during treatment with VITUZ

and this may cause you to feel dizzy, faint, lightheaded, or weak, especially when you stand up (orthostatic hypotension). Your risk of having this problem may be increased if you take VITUZ with certain other medicines that lower blood pressure. If you have any of these symptoms while taking VITUZ, sit or lie down. Do not change your body position too fast. Get up slowly from sitting or lying down.

• Adrenal gland problems. VITUZ can cause serious and life-threatening adrenal gland problems. Your healthcare provider may do blood tests to check for adrenal gland problems. Call your healthcare provider right away if you have any of these symptoms: o nausea o vomiting o not wanting to eat (anorexia) o fatigue

o weakness o dizziness o low blood pressure

The most common side effects of VITUZ include: • sleepiness • confusion • coordination problems • decrease in mental and physical performance • lack of energy • lightheadedness

• dizziness • headache • dry mouth • nausea • vomiting • constipation

These are not all the possible side effects of VITUZ. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store VITUZ? • Store VITUZ at room temperature between 68°F to 77°F (20°C to 25°C). • Store VITUZ in a tightly closed container, in a dry, cool place away from heat or direct sunlight. • Keep VITUZ and all medicines out of the reach of children. How should I dispose of VITUZ? Remove unused VITUZ from the container and mix it with an undesirable, non-toxic substance such as cat litter or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw it away in the household trash. You can also follow your state or local guidelines on how to safely throw away VITUZ. General information about the safe and effective use of VITUZ. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use VITUZ for a condition for which it was not prescribed. Do not give VITUZ to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about VITUZ that is written for health professionals.


What are the ingredients in VITUZ?Active ingredients: hydrocodone bitartrate and chlorpheniramine maleate Inactive ingredients: citric acid anhydrous, glycerin, grape flavor, methylparaben, propylene glycol, propylparaben, purified water, sodium citrate, sodium saccharin, and sucrose.

VITUZ is manufactured for Hawthorn Pharmaceuticals, Inc., Morristown, NJ 07960. VITUZ is a registered trademark of Hawthorn Pharmaceuticals, Inc. For more information, call 1-800-793-2145.

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: June 2018


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